3-Metallo substituted naphthalenes

ABSTRACT

3-Prenyl-substituted menaquinones are made by reacting a 3-metallo-2-alkyl-1,4-di(alkoxy or aralkoxy) naphthalene with a prenyl halide, and then oxidizing the resulting 3-prenyl-2-alkyl-1,4-di(alkoxy or aralkoxy) naphthalene to prepare the corresponding 3-prenyl-substituted menaquinone. The metallo substituent at the 3-position may be Li, Li/Cu, Cu or MgBr. The oxidation is advantageously conducted by the use of argentic oxide.

This is a division of application Ser. No. 565,473, filed Apr. 7, 1975,now U.S. Pat. No. 4,089,873, which is in turn a continuation-in-part ofSer. No. 540,450, filed Jan. 13, 1975, now abandoned.

This invention relates to a method of synthesizing menaquinones, andparticularly 3-prenyl-2-alkyl menaquinones. The invention includes thepreparation of 3-metallo-2-alkyl-1,4-di(alkoxy or aralkoxy)naphthalenes, and these intermediates have as the 3-metallo substituentlithium, lithium/copper copper or magnesium bromide. The inventionprovides as novel compounds the intermediates in which the 3-metallosubstituent is lithium/copper, copper or magnesium bromide. According tothe invention the 3-metallo intermediates can be reacted with a prenylhalide to prepare the corresponding 3-prenyl-2-alkyl-1,4-di(alkoxy oraralkoxy) naphthalenes, which can be oxidized to the corresponding3-prenyl-2-alkyl menaquinones. It is a further aspect of the inventionthat the oxidation is advantageously conducted by the use of argenticoxide.

The 3-prenyl-2-alkyl menaquinones prepared by this invention have thestructural formula: ##STR1## wherein R is alkyl, for instance, loweralkyl, say of 1 to about 4 or 8 atoms, preferably methyl, and wherein Zis --CH₂ CH═C(CH₃)CH₂ --_(m), --CH₂ CH₂ CH(CH₃)CH₂ --_(n) orcombinations thereof, and in which each of m and n, and their sum may be0 to about 25 or more, and frequently, each of m and n and their sum are0 to 1 to about 9 or 12. For convenience, these compounds are sometimeshereafter referred to as the MK Compounds or the MK-integer Compoundswherein the integer represents the value of m plus n plus 1. Thesecompounds have heretofore been designated as being in the vitamin Kseries, see U.S. Pat. No. 2,348,037, and can be administered tored-blooded animals in the usual manner as vitamin K compounds to combatbleeding. The MK Compounds wherein the prenyl component at the3-position carbon has the trans configuration exhibit the greatestanti-hemorrhagic activity, especially when R is methyl. By the method ofthis invention, the MK Compounds can be prepared without unduedegradation of the prenyl substituent or reactant, and thestereoconfiguration at the olefinic bond in the prenyl halide reactantor prenyl substituent can be maintained.

There have been numerous attempts to prepare prenyl-substitutedmenaquinones, but difficulties have been encountered in terms ofundesirably low yields, maintenance of the stereoconfiguration of theprenyl structure, instability of the prenyl reactant in the case ofusing it as an allylic alcohol, and side reactions such as side chainisomerization or chromal cyclization. For example, an approach to thesynthesis of MK Compounds which has been suggested involved thecondensation of 2-methyl-1,4-naphthoquinol with an allylic alcohol inthe presence of an acidic catalyst such as boron trifluoride etherate.The resulting menaquinol can be converted by mild oxidation to thecorresponding menaquinone. This suggested route for synthesizing the MKCompounds has not, however, proven to be entirely satisfactory in thatunder the acidic conditions employed for alkylation, the allylic alcoholis unstable, and thus the yields of MK Compounds based on the allylicalcohol reactant are low. Another approach which has been suggested isthrough the use of N-sulfinylamine ester of the prenyl component as thereactant to prepare MK Compounds from, for instance,2-methyl-1,4-naphthoquinol. This reaction, however, proceeds with pooryields of MK Compounds.

By the present invention it has been found that 3-prenyl-2-alkylmenaquinones can be made without encountering to undesirable extents thedifficulties previously experienced in such syntheses as noted above. Inthe new procedure the naphthalenic compound is activated at the3-position carbon with a metallo-substituent and then reacted with anappropriately functionalized prenyl halide component to prepare MKComounds. The reaction need not be conducted in the presence of theacidic or other conditions which degradate or isomerize the prenylcomponent or under conditions which unduly detract from selectiveprenylation at the 3-position carbon of the naphthalene component. Thus,in accordance with this invention, a 2-alkyl-1,4-di(alkoxy or aralkoxy)naphthalene is activated at the 3-position carbon in the form ofcorresponding 3-metallo-substituted naphthalene of the formula: ##STR2##wherein R is as defined above, R₁ and R₂ may be the same or differenthydrocarbyl groups and may be alkyl, say lower alkyl of, for instance, 1to about 4 or 8 carbon atoms, or aralkyl. The aralkyl groups may have,for example, 7 to about 10 or 12 carbon atoms, e.g. benzyl, phenethyl orother monocyclic groups. Conveniently R₁ and R₂ are methyl. M is ametal-containing substituent such as --Li, --(CuLi)_(1/2), --MgBr, --Cuand the like.

In the invention, the 3-metallo naphthalene is reacted with aprenyl-type component of the formula

    X--CH.sub.2 CH═C(CH.sub.3)CH.sub.2 --Z -- H

wherein X is halogen, preferably having an atomic number from 17 to 35,i.e., chlorine or bromine, and most preferably bromine, and wherein Z isas defined above, e.g. to provide a prenyl, geranyl, solanesyl, phytylor like group. The prenyl component is preferably of trans configurationto a major extent and most preferably is substantially entirely of thisstructure. The prenyl alkylation reaction yields compounds of theformula ##STR3## wherein R, R₁ R₂ and Z are as defined above. Theseproducts can be oxidized to the corresponding prenyl-substitutedmenaquinones. This method of synthesizing the prenyl-substitutedmenaquinones provides these products in high yields and with themaintenance of the stereoconfiguration of the prenyl reactant to a greatextent and the prenyl substituent may be substantially entirely of thesame configuration as in the prenyl halide reactant.

The prenyl alkylation reaction proceeds at room temperature. Thetemperature employed during this reaction may be lower or higher thanambient temperature, but generally may be about 5 or 10° C. to about 50°or 60° C., preferably about 15° C. to 35° C. The reaction is preferablyconducted under non-acidic conditions and can be performed in an inertatmosphere which conveniently may be nitrogen, and may be conducted inthe presence of an inert solvent, for instance, diethyl ether orpetroleum ether, and under non-acidic conditions.

The prenylated naphthalenes which are obtained in accordance with methodof this invention have protected oxygen functions at the 1 and 4-carbonpositions of the naphthalene nucleus. Keto functions at the 1 and4-positions, i.e., the corresponding menaquinones, can be obtainedwithout undue adverse effect on the prenyl substituent, by subjectingthe prenylated naphthalene to oxidation. The oxidation is preferablyeffected by, for instance, using silver (II) oxide (argentic oxide) asan oxidizing reagent and this reaction can be conducted in the presenceof an acid; although the oxidation may be done in other ways, e.g. bybubbling oxygen through a solution of the prenylated naphthalene or bytreatment of the prenylated naphthalene with ferric ion. Generally, thereaction can be conducted under relatively mild oxidation conditions.

The 3-metallo naphthalenes which may be employed in connection with thisinvention to provide the MK Compounds can be prepared from thecorresponding 3-bromo-2-alkyl-1,4-disubstituted naphthalenes. The3-bromo-2-alkyl-1,4-disubstituted naphthalene can be treated withbutyllithium in, for instance, the manner described by Snyder et al. inJ. Org. Chem., 36, 3451 (1971), herein incorporated by reference, toprepare the corresponding 3-metallo naphthalene wherein M is lithium,i.e., 3-lithio-2-alkyl-1,4-disubstituted naphthalene. The reactionbetween the 3-bromo-2alkyl-1,4-disubstituted naphthalene andbutyllithium proceeds at room temperature. An inert organic solvent suchas diethyl ether or petroleum ether may be employed in the reaction. Thesolvent may be used in quantities suitable for dissolving the organicreactants, for instance, in weight ratio to the bromo-substitutednaphthalene reactant of about 1:1 to 500:1 or more.

The 3-lithio-2-alkyl-1,4-disubstituted naphthalene compounds can beconverted to the compounds wherein M is (CuLi)_(1/2) by adding cuproushalide such as a bromide or chloride, preferably cuprous bromide, to the3-lithio-naphthalene compound. The cuprous halide is frequently providedin an amount of about 0.3 to 0.7, preferably about 0.4 to 0.6, mole ofcuprous ion per mole of the 3-lithio-naphthalene compound. The reactionto prepare 3-lithio-2-alkyl-1,4-disubstituted naphthyl cuprate isconveniently conducted at room temperature, i.e., about 15° to 35° C.,under agitation. The time of the reaction is brief, for instance, goodconversion may be obtained in about 0.5 to 50 minutes. The reaction maybe conducted in the presence of an inert solvent, for instance, drytetrahydrofuran. The solvent may be used in quantities suitable fordissolving the organic reactants, for instance, in a weight ratio ofsolvent to the naphthalene derivative reactant of about 1:1 to 500:1 ormore.

The 3-bromo-2-alkyl-1,4-disubstituted naphthalenes may alternatively beconverted to the corresponding Grignard reagent, that is, where M ismagnesium bromide. The conversion may be effected by adding magnesiummetal to the 3-bromo-2-alkyl-1,4-disubstituted naphthalene. Preferably,the magnesium metal used is freshly prepared in finely divided form, forinstance, as fresh magnesium filings. Frequently, the molar ratio ofmagnesium metal to the 3bromo reactant is about 0.9 to 2, preferablyabout 0.95 to 1.2. The reaction proceeds at room temperature; however,elevated or reduced temperatures may be employed, for instance, fromabout 5° to 50° C., preferably about 10° to 35° C. The reaction can beconducted in an inert solvent such as diethyl ether or petroleum ether.The solvent may be used in quantities suitable for dissolving theorganic reactants, for instance, in a weight ratio of solvent to thenaphthalene derivative reactant of about 1:1 to 500:1, or more.

The Grignard reagent, 2-alkyl-1,4-disubstituted-naphthyl-3-magnesiumbromide, can be treated with a cuprous halide, such as a bromide orchloride, preferably cuprous bromide, to prepare the correspondingcompounds wherein M is copper, i.e., a 3-cupro-2-alkyl-1,4-disubstitutednaphthalene. The cuprous halide is conveniently provided in a molarratio to the Grignard reagent of about 0.9:1 to 2:1, preferably about0.95:1 to 1.2:1. The reaction proceeds at room temperature, but higheror lower reaction temperatures may be employed, for instance, from about5° to 50° C., preferably about 10° to 35° C. The reaction may beconducted in an inert solvent such as diethyl ether or petroleum ether,in quantities suitable for dissolving the organic reactants, forinstance, in a weight ratio of solvent to the naphthalene derivativereactant of about 1:1 to 500:1.

The 3-metallo-2-alkyl-1,4-disubstituted naphthalenes are reacted with aprenyl-type compound, e.g. a prenyl halide such as a chloride orbromide, to achieve prenylation and obtain the 1,4-diether of the MKCompounds. A prenyl-type halide may be obtained from the correspondingprenyl alcohol by conventional procedures such as that disclosed byIsler, et al., Helv. Chem. Acta, Volume 39, page 897 (1956), hereinincorporated by reference. The corresponding alcohols are frequentlymore readily available than the prenyl halides. Commonly availableprenyl alcohols include trans-geraniol, cis-nerol, farnesol, phytol, andsolanesol. The prenyl-type compound may be substituted with one or morehydrocarbyl-containing groups in place of a hydrogen bonded to a carbonatom. The hydrocarbyl-containing group may be, for instance, alkyl offrom 1 to about 30 carbon atoms.

Since often the prenyl-type halide is the more valuable of the startingmaterials, the 3-metallo-2-alkyl-1,4-disubstituted naphthalene maydesirably be employed in stochiometric or in excess of stoichiometricamounts. For instance, the molar ratio of prenyl halide to 3-metallonaphthalene derivative reactant may be about 0.5:1 to 2:1, preferablyabout 0.95:1 to 1.5:1. The reaction may proceed rapidly, and frequentlythe duration of the reaction is about 0.1 to 20 hours.

The product of the reaction involving the prenyl-type halide and3-metallo-2-alkyl-1,4-disubstituted naphthalene is a correspondng1,4-diether naphthalene which can be converted to the MK Compounds byoxidation. By one method, the oxidation may be carried out using areaction mixture containing silver (II) oxide as an oxygen source, and astrong acid. The acid is preferably a mineral acid such as nitric acid,sulfuric acid, or hydrochloric acid. The reaction proceeds quickly atroom temperature, often in less than about 2 hours, and reactiontemperatures of about 5° to 50° C., preferably about 15° to 35° C., areemployed.

The silver (II) oxide may be provided in the reaction mixture in a molarratio (calculated as AgO) to the diether naphthalene reactant of about1:1 to 5:1, preferably about 2:1 to 3:1, and high conversions toMK-2Compound wherein R is methyl have been observed using a ratio ofabout 2.2:1. Lesser amounts of oxidizing agent could be employed;however, it is often commercially advantageous to supply the silver (II)oxide in stoichiometric excess. The acid can be provided in a molaramount of about 1 to 5, preferably about 2 to 4, times the amount ofdiether naphthalene reactant. The oxidation is preferably conducted inthe presence of a solvent such as dioxane. The solvent may be providedin an amount suitable for dissolving the organic reactants, e.g. about 5to 1000, preferably about 50 to 500, times the weight amount of diethernaphthalene. In addition to the water which may be supplied with theacid, water may be used with the solvent, for instance, in a volumeratio of about 0.01:1 to 1:1 to the solvent.

The recovery of the MK Compounds may be effected by conventional means,for instance, by extraction with petroleum ether and water or aqueoussalt solution. Column chromatography using, for instance, kieselgelabsorbent, is also useful.

The MK Compounds may be substituted at one or more of the 5,6,7 and 8position with, for instance, lower alkyl or lower alkoxy having 1 toabout 8 carbon atoms. Such substituted MK Compounds may be preparedemploying a corresponding, substituted naphthoquinol or naphthoquinoneas the starting material where the substituent is non-reactive duringthe synthesis of the MK compound, or the substituent may beappropriately blocked during the reaction and later recovered to obtainthe desired, substituted MK Compound.

In the following examples which illustrate the invention, the reactionsare conducted at room temperature and under a nitrogen atmosphere unlessotherwise indicated, and all parts and percentages are by weight unlessotherwise noted.

EXAMPLE 1 3.31 Grams of tri-n-butylphosphine is added dropwise to asolution of 1.54 grams of trans-geraniol (99 percent) in 20 millilitersof carbon tetrachloride which has been distilled from P₂ O₅. Thereaction mixture is then diluted with petroleum ether and the solvent isdecanted from the residual viscous tri-n-butylphosphine oxide. After thesolvent is removed, the residue is purified by distillation at 70° C.and 1 millimeter pressure to yield essentially pure trans-geranylchloride. EXAMPLE 2

About 281 milligrams of 3-bromo-2-methyl-1,4-dimethyloxynaphthalene (1.0millimole) is dissolved in two milliliters of petroleum ether and amixture of about 64 milligrams of butyllithium (1.0 millimole) in 0.62milliliters of hexane is added thereto. A white precipitate results andwater is added. 3-Lithio-2-methyl-1,4-dimethpoxynaphthalene is in theether layer and is recovered.

EXAMPLE 3

About 104 milligrams of 3-lithio-2-methyl-1,4-dimethoxynaphthalene (0.5millimole) prepared as in Example 2, is quenched with 0.5 milliliter ofdeuteium oxide, and the crude product is obtained by extraction withpetroleum ether. Nmr integration of the 3-aromatic proton versus the5,6,7,8-protons indicated 99 percent deuterium at the 3-position.

EXAMPLE 4

Approximately 36 milligrams of cuprous bromide (0.25 millimole) areadded to about 104 milligrams of3-lithio-2-methyl-1,4-dimethoxynaphthalene (0.5 millimole) prepared asin Example 2, in a petroleum ether solvent. The reaction mixture issubjected to vigorous stirring for about 15 minutes and a brownishprecipitate forms in the reaction mixture. The brownish precipitate islithium 3-(2-methyl-1,4-dimethoxy) dinaphthyl cuprate.

EXAMPLE 5

About 12 milligrams of freshly prepared magnesium filings (0.5millimole) are added to about 141 milligrams of3-bromo-2-methyl-1,4-dimethoxynaphthalene (0.5 millimole) in 1milliliter of dry tetrahydrofuran. The mixture is stirred for 3 hours atroom temperature. The resulting clear solution contains2-methyl-1,4-dimethoxynaphthalene-3-magnesium bromide.

EXAMPLE 6

2-Methyl-1,4-dimethoxynaphthalene-3-magnesium bromide is quenched withdeuterium oxide, and 2-methyl-1,4-dimethoxynaphthalene is obtained byextraction with petroleum ether. Nmr integration of the 3-aromaticproton versus the 5,6,7,8-protons indicated 97 percent deuterium at the3-position.

EXAMPLE 7

About 153 milligrams of 2-methyl-1,4-dimethoxynaphthalene-3-magnesiumbromide (0.5 millimole) are mixed with 72 milligrams of cuprous bromide(0.5 millimole) in a tetrahydrofuran solvent and after a brief stirringof the reaction mixture, a gelatinous precipitate is formed which uponfurther stirring provides a homogeneous clear solution of3-cupro-2-methyl-1,4-dimethoxynaphthalene in tetrahydrofuran.

EXAMPLE 8

About 86 milligrams of trans-geranyl chloride (0.5 millimole) preparedas in Example 1 are added to about 208 milligrams of3-lithio-2-methyl-1,4-dimethoxynaphthalene (0.5 millimole) in a reactionvessel. The reaction vessel is sealed in vacuo. The reaction mixture isheated at 50° C. for 68 hours after which the vessel is opened and thegeranyl chloride which is unreacted is determined to be 80 percent bygas chromatography. The reaction mixture is diluted with petroleumether, the salts are removed by centrifugation, and crude product isobtained by evaporation of solvents. Column chromatography using Camagkieselgel absorbent gave 17 milligrams of the dimethyl ether of MK-2Compound wherein R is methyl and 62 milligrams of2-methyl-1,4-dimethoxynaphthalene.

EXAMPLE 9

A mixture of 108 milligrams of trans-geranyl bromide (0.5 millimole) andabout 236 milligrams of lithium 3-(2-methyl-1,4-dimethoxy)dinaphthalenecuprate (0.5 millimole) is added to a reaction vessel. The reactionvessel is sealed as in Example 8 and after stirring for 17 hours thereaction mixture is partitioned between petroleum ether and water. Uponevaporation of the organic solvent a crude product is obtained which ischromatographed using essentially the same procedure described inExample 8 to yield 125 milligrams of the dimethyl ether of MK-2 Compoundwherein R is methyl.

EXAMPLE 10

About 108 milligrams of trans-geranyl bromide (0.5 millimole) is addedto about 168 milligrams of 2-methyl-1,4-dimethoxynaphthalene-3-magnesiumbromide (0.55 millimole) in a 1.1 molar solution of tetrahydrofuran. Thereaction is conducted in essentially the same manner as described inExample 9 and after 17 hours the reaction mixture is diluted withpetroleum ether. The salts are removed by centrifugation and thesolvents are evaporated to provide a crude product which ischromatographed to yield a mixture of 156 milligrams of the dimethylether of MK-2 Compound wherein R is methyl and minor amounts of3-bromo-2-methyl-1,4-dimethoxynaphthalene and2-methyl-1,4-dimethoxynaphthalene. The dimethyl ether of MK-Compound isnot separated from the 3-bromo-2-methyl-1,4-dimethoxynaphthalene.

EXAMPLE 11

To 84.5 milligrams of the product mixture provided by Example 10 (about0.254 millimole of total dimethoxy naphthalene compounds) is added 68.2milligrams silver (II) oxide (0.55 millimole), 2.5 milliliters ofdioxane and 0.25 milliliters of water. 92 Microliters of 6.2N nitricacid are added to the mixture to accomplish the oxidation. The reactionmixture is then partitioned between 19 milliliters of petroleum etherand 2 milliliters of water. The organic phase is extracted twice with 3milliliters of water and then is evaporated to provide a residue. Theresidue is column chromatographed to provide 60 milligrams of trans-MK-2Compound wherein R is methyl.

EXAMPLE 12

The procedures of Examples 10 and 11 are essentially repeated exceptemploying cis-neryl bromide instead of transgeranyl bromide. In theoxidation, 34 milligrams of the dimethyl ether of MK-2 Compound and3-bromo-2-methyl-1,4-dimethoxynaphthalene (about 0.1 millimole of totaldimethoxy naphthalene compounds); 27 milligrams of silver (II) oxide(0.22 millimole); 1 milliliter of dioxane; 0.1 milliliter of water; and38 microliters of 6.2N nitric acid are employed. About 24 milligrams ofcis-MK-2 Compound wherein R is methyl are obtained (85 percent cis).

EXAMPLE 13

About 108 milligrams of trans-geranyl bromide (0.5 millimole) is addedto about 132 milligrams of 3-cupro-2-methyl-1,4-dimethoxynaphthalene(0.5 millimole) and an immediate precipitation of cuprous bromideoccurs. The reaction mixture is stirred for one hour and then dilutedwith petroleum ether and the product is isolated as in Example 10 toprovide a mixture of 138 milligrams of the dimethyl ether of MK-2Compound wherein R is methyl and 10 milligrams of3-bromo-2-methyl-1,4-dimethoxynaphthalene.

This mixture is oxidized using essentially the same procedure describedin Example 11 except using 2.5 mole equivalents of silver (II) oxide and2.6 mole equivalents of nitric acid to provide trans-MK-2 Compoundwherein R is methyl (97 percent trans.)

EXAMPLE 14

Essentially the same procedure is followed as set forth in Example 10except that 3-lithio-2-methyl-1,4-dimethoxynaphthalene is employedinstead of 2-methyl-1,4-dimethoxynaphthalene-3-magnesium bromide. Thedimethyl ether of MK-2 Compound wherein R is methyl is prepared.

EXAMPLE 15

Essentially the same procedure is followed in this example as used inExample 10 except that trans-geranyl chloride is employed instead oftrans-geranyl bromide. The dimethyl ether of MK-2 Compound wherein R ismethyl is prepared.

EXAMPLE 16

A mixture of about 113 milligrams of2-methyl-1,4-dimethoxynaphthalene-3-magnesium bromide (0.37 millimole)and 208 milligrams trans-solanesyl bromide (0.3 millimole) is prepared.The reaction mixture is permitted to stand for 18 hours and petroleumether is then added to the mixture. The precipitate of salts is removedand the residue obtained by solvent evaporation is resolved by columnchromatography using Camag kieselgel absorbent to provide 232 milligramsof the dimethyl ether of MK-9 Compound.

The dimethyl ether of MK-9 Compond in an amount of 163 milligrams (about0.2 millimole total dimethoxynaphthalene) is mixed with 62 milligrams ofsilver (II) oxide in 3 milliliters of dioxane and 0.2 milliliter ofwater. 84 Microliters of 6.2N nitric acid are added to the mixture, andthe reaction mixture is stirred until a complete solution is obtained.The reaction mixture is then partitioned between 10 milliliters ofpetroleum ether and 2 milliliters of water. The organic phase is washedtwice with 3 milliliters of water and the solvent is evaporated. Theresidue is resolved by column chromatography to yield 110 milligrams ofMK-9 (98 percent Δ² -trans). The residue also contains 35 milligrams ofthe starting material.

When the oxidation reaction is repeated using 3.0 molar equivalents ofsilver (II) oxide and 3.1 molar equivalents of nitric acid, essentiallycomplete consumption of the dimethyl ether of MK-9 wherein R is methyloccurs.

EXAMPLE 17

2-Methyl-3-bromomagnesio-1,4-dimethoxynaphthalene (0.55 mmol, 1.1M) isprepared as in Example 5, and phytyl bromide (0.50 mmol) is addedthereto. After 17 hours the reaction mixture is diluted with petroleumether, the salts are removed by centrifugation, and the solventsevaporated to give the crude product which is chromatographed on silicato give 2-methyl-3-trans-phytyl-1,4-dimethoxynaphthalene. This dimethylether (0.25 mmol) and argentic oxide (0.55 mmol) are mixed, and dioxane(2.5 ml) and water (0.25 ml) are added. Addition of nitric acid (6.2N,92 microliters, 0.57 mmol) accomplishes the oxidation. The reactionmixture is then partitioned between petroleum ether (19 ml) and water(2ml), and the organic phase is extracted twice with water using 3 mleach time, and then evaporated. Chromatography of the residue gives an87% yield of trans -phylloquinone.

It is claimed:
 1. Compounds of the formula ##STR4## wherein R is loweralkyl and R₁ and R₂ are lower alkyl, or aralkyl of 7 to about 12 carbonatoms, and M is selected from the group consisting of (CuLi)_(1/2) andCu.
 2. The compounds of claim 1 wherein R is methyl.
 3. The compounds ofclaim 2 wherein R₁ and R₂ are methyl.
 4. A method of preparinglithium-3-naphthyl cuprate of the formula ##STR5## wherein R is loweralkyl, R₁ and R₂ are lower alkyl, or aralkyl of 7 to about 12 carbonatoms, comprising reacting cuprous halide with 3-lithio-naphthalene ofthe formula ##STR6## in a molar ratio of cuprous halide to3-lithio-naphthalene of from about 0.3 to 0.7 to prepare thelithium-3-naphthalene cuprate.
 5. The method of claim 4 wherein thecuprous halide is cuprous bromide.
 6. The method of claim 5 wherein thereaction is conducted with about 0.4 to 0.6 mole of cuprous bromide permole of the 3-lithio-naphthalene.
 7. The method of claim 5 wherein R, R₁and R₂ are methyl.
 8. A method of preparing 3-cupro-naphthalene of theformula ##STR7## wherein R is lower alkyl, R₁ and R₂ are lower alkyl, oraralkyl of 7 to about 12 carbons, comprising reactingnaphthyl-3-magnesium bromide of the formula ##STR8## with cuprous halidein a molar ratio of from about 0.9 to 2 moles of cuprous halide per moleof naphthyl-3-magnesium bromide to prepare the 3-cupro-naphthalene. 9.The method of claim 8 wherein R, R₁ and R₂ are methyl.
 10. The method ofclaim 9 wherein the reaction is conducted with about 0.95 to 1.2 molesof cuprous halide per mole of naphthyl-3-magnesium bromide.
 11. Themethod of claim 10 in which the cuprous halide is cuprous bromide. 12.The method of claim 11 wherein the reaction is conducted in the presenceof tetrahydrofuran solvent.